Comprehensive Profiling of Hypoxia-Related miRNAs Identifies miR-23a-3p Overexpression as a Marker of Platinum Resistance and Poor Prognosis in High-Grade Serous Ovarian Cancer

• Main Authors: Paola Todeschini, Elisa Salviato, Chiara Romani, Vittoria Raimondi, Francesco Ciccarese, Federico Ferrari, Germana Tognon, Sergio Marchini, Maurizio D’Incalci, Laura Zanotti, Antonella Ravaggi, Franco Odicino, Enrico Sartori, Donna M. D’Agostino, Michele Samaja, Chiara Romualdi, Eliana Bignotti
• Format: Article
• Language: English
• Published: MDPI AG 2021-07-01
• Series: Cancers
• Subjects: miRNA; hypoxia; ovarian cancer; platinum response; prognostic marker; miR-23a-3p
• Online Access: https://www.mdpi.com/2072-6694/13/13/3358

The onset of chemo-resistant recurrence represents the principal cause of high-grade serous ovarian carcinoma (HGSOC) death. HGSOC masses are characterized by a hypoxic microenvironment, which contributes to the development of this chemo-resistant phenotype. Hypoxia regulated-miRNAs (HRMs) represent a molecular response of cancer cells to hypoxia and are involved in tumor progression. We investigated the expression of HRMs using miRNA expression data from a total of 273 advanced-stage HGSOC samples. The miRNAs associated with chemoresistance and survival were validated by RT-qPCR and target prediction, and comparative pathway analysis was conducted for target gene identification. Analysis of miRNA expression profiles indicated miR-23a-3p and miR-181c-5p over-expression as associated with chemoresistance and poor PFS. RT-qPCR data confirmed upregulation of miR-23a-3p in tumors from chemoresistant HGSOC patients and its significant association with shorter PFS. In silico miR-23a-3p target prediction and comparative pathway analysis identified platinum drug resistance as the pathway with the highest number of miR-23a-3p target genes. Among them, APAF-1 emerged as the most promising, being downregulated in platinum-resistant patients and in HGSOC chemo-resistant cells. These results highlight miR-23a-3p as a potential biomarker for HGSOC platinum response and prognosis and the miR23a-3p/APAF1 axis as a possible target to overcome platinum-resistance.